tbuckley/cabot-search huggingface dataset:
Anlotinib in Locally Advanced or Metastatic Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Randomized, Double-Blind, Multicenter Phase II Trial
Authors: Yihebali Chi, Xiangqian Zheng, Yuan Zhang, Feng Shi, Ying Cheng, Zhuming Guo, Minghua Ge, Jianwu Qin, Jiewu Zhang, Zhendong Li, Xiaohong Zhou, Rui Huang, Xiaohong Chen, Hui Liu, Ruochuan Cheng, Zhengang Xu, Dapeng Li, Pingzhang Tang, Ming Gao
Journal: Clinical Cancer Research (2023)

Alhough antiangiogenic agents are the bedrock of treatment for radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC), novel antiangiogenic agents with optimized features like greater target-binding affinities and more favorable pharmacokinetics profile are needed. This phase II randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of anlotinib, a multikinase inhibitor, for RAIR-DTC.Patients (ages between 18 and 70 years) with pathologically confirmed locally advanced or metastatic RAIR-DTC were enrolled and randomly received 12 mg anlotinib once daily or placebo on day 1 to 14 every 3 weeks. Patients on placebo were allowed to receive open-label anlotinib after disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS) and safety.Between September 2015 and August 2018, 76 and 37 patients randomly received anlotinib and placebo, respectively. Patients receiving anlotinib had a significantly longer median PFS [40.5 months, 95% confidence interval (CI), 28.3-not estimable (NE) versus placebo 8.4 months, 95% CI, 5.6-13.8; HR = 0.21, 95% CI, 0.12-0.37, P < 0.001], meeting the primary endpoint. OS was still immature, with a trend of benefit with anlotinib (HR = 0.57, 95% CI, 0.29-1.12). All patients in the anlotinib group experienced adverse events (AE); 8 (10.5%) discontinued treatment due to AEs.Anlotinib demonstrated promising efficacy and favorable tolerance in the treatment of locally advanced or metastatic RAIR-DTC, supporting further research to establish its role in the treatment of this serious disease.
Optical Control of Cardiac Rhythm by In Vivo Photoactivation of an ERG Channel Peptide Inhibitor
Authors: Jérôme Montnach, Hugo Millet, Antoine Persello, Hervé Meudal, Stephan De Waard, Pietro Mesrica, Barbara Ribeiro, Jérémie Richard, Agnès Hivonnait, Agnès Tessier, Benjamin Lauzier, Flavien Charpentier, Matteo E. Mangoni, Céline Landon, Chris Jopling, Michel De Waard
Journal: Circulation Research (2023)

◼ photochemotherapy ◼ potassium channels ◼ zebrafish
FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor–Positive, HER2-Negative Advanced or Metastatic Breast Cancer
Authors: Jennifer J. Gao, Christy L. Osgood, Zhou Feng, Erik W. Bloomquist, Shenghui Tang, C.J. George Chang, Tiffany K. Ricks, Sherry C. Hou, William F. Pierce, Donna R. Rivera, Richard Pazdur, Paul G. Kluetz, Laleh Amiri-Kordestani
Journal: Clinical Cancer Research (2023)

Abstract On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in adult patients, or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib + AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single-arm, multicenter clinical trial, in which 39 male patients (n = 3,246 total patients) received ribociclib + letrozole + goserelin/leuprolide. The overall response rate (ORR) based on confirmed responses in male patients with measurable disease at baseline was 46.9% [95% confidence interval (CI), 29.1–65.3], consistent with an ORR of 43.6% (95% CI, 41.5–45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib + ET. The efficacy of ribociclib + fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib + fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib + AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights.
Response to Kang et al.
Authors: Carlos A Garcia-Prieto, Veronica Davalos, Manel Esteller
Journal: JNCI Journal of the National Cancer Institute (2023)

We are glad to learn that Kang et al (1) have successfully replicated our findings, confirming that a profile of DNA methylation in CAR-T cells (termed EPICART signature in our case) is enriched in naïve T-cell subsets that are likely associated with improved clinical response in B-cell malignancies.Interestingly, the confirmation of our data occurs despite these authors did not use the authentic EPICART signature that we obtained using a rigorously trained, supervised classification model based on ridge-regularized logistic regression to accurately predict clinical response; instead Kang et al (1) used a basic hierarchical clustering (hereafter denominated PseudoEpicart).It is noteworthy that the PseudoEpicart
T-cell phenotype including CD57+ T follicular helper cells in the tumor microenvironment correlate with a poor outcome in follicular lymphoma
Authors: Zhi-Zhang Yang, Hyo Jin Kim, Hongyan Wu, Xinyi Tang, Yue Yu, Jordan Krull, Daniel P. Larson, Raymond M. Moore, Matthew J. Maurer, Kevin D. Pavelko, Shahrzad Jalali, Joshua C. Pritchett, Rekha Mudappathi, Junwen Wang, Jose C. Villasboas, Patrizia Mondello, Anne J. Novak, Stephen M. Ansell
Journal: Blood Cancer Journal (2023)

Abstract T-lymphocytes are prevalent in the tumor microenvironment of follicular lymphoma (FL). However, the phenotype of T-cells may vary, and the prevalence of certain T-cell subsets may influence tumor biology and patient survival. We therefore analyzed a cohort of 82 FL patients using CyTOF to determine whether specific T-cell phenotypes were associated with distinct tumor microenvironments and patient outcome. We identified four immune subgroups with differing T-cell phenotypes and the prevalence of certain T-cell subsets was associated with patient survival. Patients with increased T cells with early differentiation stage tended to have a significantly better survival than patients with increased T-cells of late differentiation stage. Specifically, CD57 + T FH cells, with a late-stage differentiation phenotype, were significantly more abundant in FL patients who had early disease progression and therefore correlated with an inferior survival. Single cell analysis (CITE-seq) revealed that CD57 + T FH cells exhibited a substantially different transcriptome from CD57 − T FH cells with upregulation of inflammatory pathways, evidence of immune exhaustion and susceptibility to apoptosis. Taken together, our results show that different tumor microenvironments among FL patients are associated with variable T-cell phenotypes and an increased prevalence of CD57 + T FH cells is associated with poor patient survival.
Ambient Air Pollutants and Olfaction among Women 50–79 Years of Age from the Sister Study
Authors: Zichun Cao, Aiwen Yang, Alexandra J. White, Frank Purdy, Chenxi Li, Zhehui Luo, Aimee A. D’Aloisio, Lourdes Suarez, Sandra Deming-Halverson, Jayant M. Pinto, Jiu-Chiuan Chen, Emily J. Werder, Joel D. Kaufman, Dale P. Sandler, Honglei Chen
Journal: Environmental Health Perspectives (2023)

Poor olfaction is common in older adults and may have profound adverse implications on their health. However, little is known about the potential environmental contributors to poor olfaction.We investigated ambient fine particulate matter [PM ≤2.5μm in aerodynamic diameter (PM2.5)] and nitrogen dioxide (NO2) in relation to poor olfaction in middle-aged to older women.The Sister Study is a nationwide cohort of 50,884 women in the United States with annual average air pollutant exposures estimated based on participants' residences from enrollment (2003-2009) through 2017. This analysis was limited to 3,345 women, 50-79 years of age as of January 2018, who completed the Brief Smell Identification Test (B-SIT) in 2018-2019. Poor olfaction was defined as a B-SIT score of ≤9 in the primary analysis. We conducted multivariable logistic regressions, accounting for covariates and study sampling design.Overall, we found little evidence for associations of air pollutants with poor olfaction. The odds ratio (OR) and 95% confidence interval (CI) of poor olfaction for each interquartile range (IQR) increment of air pollutants in 2006 were 1.03 (95% CI: 0.91, 1.17) for PM2.5 (per 3.3 μg/m3) and 1.08 (95% CI: 0.96, 1.22) for NO2 (per 5.7 ppb). Results were similar in the analyses using the most recent (2017) or the cumulative average (2006-2017) air pollutant exposure data. Secondary analyses suggested potential association in certain subgroups. The OR per IQR was 1.35 (95% CI: 1.11, 1.65) for PM2.5 among younger participants (<54.2 years of age) and 1.87 (95% CI: 1.29, 2.71) for NO2 among current smokers.This study did not find convincing evidence that air pollutants have lasting detrimental effects on the sense of smell of women 50-79 years of age. The subgroup analyses are exploratory, and the findings need independent confirmation. https://doi.org/10.1289/EHP12066.
Telemedicine Visits in US Skilled Nursing Facilities
Authors: Agne Ulyte, Ateev Mehrotra, Andrew D. Wilcock, Gillian K. SteelFisher, David C. Grabowski, Michael L. Barnett
Journal: JAMA Network Open (2023)

Telemedicine in skilled nursing facilities (SNFs) has the potential to improve access and timeliness of care. During the COVID-19 pandemic in 2020 to 2022, telemedicine coverage expanded, but little is known about patterns of use in SNFs.To describe patterns of telemedicine use in SNFs.This cohort study used 2018 to 2022 Medicare fee-for-service claims and Minimum Data Set 3.0 records to identify short- and long-term care SNF residents. Clinician visits were grouped into routine SNF visits (ie, regular primary care within SNF) and other outpatient visits (ie, with non-SNF affiliated primary and specialty care clinicians). Using a difference-in-differences approach, assessments included whether off-hours visits (measured as weekend visits), new specialist visits, psychiatrist visits, or visits for residents with limited mobility changed differentially between 2018 to 2019 and 2020 to 2021 for SNFs with high compared with low telemedicine use in 2020.Telemedicine adoption at SNF after 2020.Number and proportion of telemedicine SNF and outpatient visits.Across 15 434 SNFs and 4 463 591 residents from the period January 2019 through June 2022 (mean [SD] age, 79.7 [11.6] years; 61% female in 2020), telemedicine visits increased from 0.15% in January 2019 to February 2020 to 15% SNF visits and 25% outpatient visits in May 2020. By 2022, telemedicine dropped to 2% of SNF visits and 8% of outpatient visits. The proportion of SNFs with any telemedicine visits annually dropped from 91% in 2020 to 61% in 2022. The facilities with high telemedicine use were more likely to be rural (adjusted odds ratio vs urban, 2.06; 95% CI, 1.77 to 2.40). Psychiatry visits differentially increased in high vs low telemedicine-use SNFs (20.2% relative increase; 95% CI, 1.2% to 39.2%). In contrast, there was little change in outpatient visits for residents with limited mobility (7.2%; 95% CI, -0.1% to 14.6%) or new specialist visits (-0.7%; 95% CI, -2.5% to 1.2%).In this cohort study of SNF residents, telemedicine was rapidly adopted in early 2020 but subsequently stabilized at a low use rate that was nonetheless higher than before 2020. Higher telemedicine use in SNFs was associated with improved access to psychiatry visits in SNFs. A policy to encourage continued telemedicine use may facilitate further access to important services as the technology matures.
Acute Myeloid Leukemia
Authors: Bob Lowenberg, James R. Downing, Alan Burnett
Journal: New England Journal of Medicine (1999)

Acute myeloid leukemia (AML) is characterized by an increase in the number of myeloid cells in the marrow and an arrest in their maturation, frequently resulting in hematopoietic insufficiency (granulocytopenia, thrombocytopenia, or anemia), with or without leukocytosis. In the United States, the annual incidence of AML is approximately 2.4 per 100,000,1 and it increases progressively with age, to a peak of 12.6 per 100,000 adults 65 years of age or older. Until the 1970s, the diagnosis was based solely on the pathological and cytologic examination of bone marrow and blood. Five-year survival rates during this period were less than 15 . . .
Activation of endothelial TRPM2 exacerbates blood–brain barrier degradation in ischemic stroke
Authors: Pengyu Zong, Jianlin Feng, Cindy X Li, Evan R Jellison, Zhichao Yue, Barbara Miller, Lixia Yue
Journal: Cardiovascular Research (2023)

Damage of the blood-brain barrier (BBB) is a hallmark of brain injury during the early stages of ischemic stroke. The subsequent endothelial hyperpermeability drives the initial pathological changes and aggravates neuronal death. Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable nonselective cation channel activated by oxidative stress. However, whether TRPM2 is involved in BBB degradation during ischemic stroke remains unknown. We aimed to investigate the role of TRPM2 in BBB degradation during ischemic stroke and the underlying molecular mechanisms.
Sex-biased TGFβ signalling in pulmonary arterial hypertension
Authors: Marius Wits, Clarissa Becher, Frances de Man, Gonzalo Sanchez-Duffhues, Marie-José Goumans
Journal: Cardiovascular Research (2023)

Abstract Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder leading to pulmonary hypertension and, often fatal, right heart failure. Sex differences in PAH are evident, which primarily presents with a female predominance and increased male severity. Disturbed signalling of the transforming growth factor-β (TGFβ) family and gene mutations in the bone morphogenetic protein receptor 2 (BMPR2) are risk factors for PAH development, but how sex-specific cues affect the TGFβ family signalling in PAH remains poorly understood. In this review, we aim to explore the sex bias in PAH by examining sex differences in the TGFβ signalling family through mechanistical and translational evidence. Sex hormones including oestrogens, progestogens, and androgens, can determine the expression of receptors (including BMPR2), ligands, and soluble antagonists within the TGFβ family in a tissue-specific manner. Furthermore, sex-related genetic processes, i.e. Y-chromosome expression and X-chromosome inactivation, can influence the TGFβ signalling family at multiple levels. Given the clinical and mechanistical similarities, we expect that the conclusions arising from this review may apply also to hereditary haemorrhagic telangiectasia (HHT), a rare vascular disorder affecting the TGFβ signalling family pathway. In summary, we anticipate that investigating the TGFβ signalling family in a sex-specific manner will contribute to further understand the underlying processes leading to PAH and likely HHT.
Macrophage heterogeneity in the single-cell era: facts and artifacts
Authors: David A. Hume, Susan M. Millard, Allison R. Pettit
Journal: Blood (2023)

Abstract In this spotlight, we review technical issues that compromise single-cell analysis of tissue macrophages, including limited and unrepresentative yields, fragmentation and generation of remnants, and activation during tissue disaggregation. These issues may lead to a misleading definition of subpopulations of macrophages and the expression of macrophage-specific transcripts by unrelated cells. Recognition of the technical limitations of single-cell approaches is required in order to map the full spectrum of tissue-resident macrophage heterogeneity and assess its biological significance.
Genetic alterations and MRD refine risk assessment for <i>KMT2A</i>-rearranged B-cell precursor ALL in adults: a GRAALL study
Authors: Rathana Kim, Hugo Bergugnat, Cédric Pastoret, Florence Pasquier, Emmanuel Raffoux, Lise Larcher, Marie Passet, Nathalie Grardel, Eric Delabesse, Susanne Kubetzko, Aurélie Caye-Eude, Claus Meyer, Rolf Marschalek, Marine Lafage-Pochitaloff, Anne Thiebaut-Bertrand, Marie Balsat, Martine Escoffre-Barbe, Sabine Blum, Michael Baumann, Anne Banos, Nicole Straetmans, Maria-Pilar Gallego-Hernanz, Yves Chalandon, Carlos Graux, Jean Soulier, Thibaut Leguay, Mathilde Hunault, Françoise Huguet, Véronique Lhéritier, Hervé Dombret, Nicolas Boissel, Emmanuelle Clappier
Journal: Blood (2023)
<i>BRAF</i> V600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis
Authors: Aldo A. Acosta-Medina, Paul G. Kemps, Timo C. E. Zondag, Jithma P. Abeykoon, Jelske Forma-Borst, Eline C. Steenwijk, Elizabeth A. M. Feijen, Jop C. Teepen, N. Nora Bennani, Susan M. Schram, Mithun V. Shah, Caroline Davidge-Pitts, Matthew J. Koster, Jay H. Ryu, Robert Vassallo, W. Oliver Tobin, Jason R. Young, Surendra Dasari, Karen Rech, Aishwarya Ravindran, Arjen H. G. Cleven, Robert M. Verdijk, Carel J. M. van Noesel, Brian V. Balgobind, Gerrit Joan Bouma, Peerooz Saeed, Jos A. M. Bramer, Ruben A. L. de Groen, Joost S. P. Vermaat, Michiel A. J. van de Sande, Egbert F. Smit, Anton W. Langerak, Tom van Wezel, Sanne H. Tonino, Cor van den Bos, Jan A. M. van Laar, Ronald S. Go, Gaurav Goyal, Astrid G. S. van Halteren
Journal: Blood (2023)
Pathophysiology, diagnosis, and management of neuroinflammation in covid-19
Authors: Rachel L Brown, Laura Benjamin, Michael P Lunn, Tehmina Bharucha, Michael S Zandi, Chandrashekar Hoskote, Patricia McNamara, Hadi Manji
Journal: BMJ (2023)

Abstract Although neurological complications of SARS-CoV-2 infection are relatively rare, their potential long term morbidity and mortality have a significant impact, given the large numbers of infected patients. Covid-19 is now in the differential diagnosis of a number of common neurological syndromes including encephalopathy, encephalitis, acute demyelinating encephalomyelitis, stroke, and Guillain-Barré syndrome. Physicians should be aware of the pathophysiology underlying these presentations to diagnose and treat patients rapidly and appropriately. Although good evidence has been found for neurovirulence, the neuroinvasive and neurotropic potential of SARS-CoV-2 is limited. The pathophysiology of most complications is immune mediated and vascular, or both. A significant proportion of patients have developed long covid, which can include neuropsychiatric presentations. The mechanisms of long covid remain unclear. The longer term consequences of infection with covid-19 on the brain, particularly in terms of neurodegeneration, will only become apparent with time and long term follow-up.
Horizontally Transferred DNA in the Genome of the Fungus <i>Pyricularia oryzae</i> is Associated With Repressive Histone Modifications
Authors: Natsuki Kobayashi, Thach An Dang, Kieu Thi Minh Pham, Luis B Gómez Luciano, Ba Van Vu, Kosuke Izumitsu, Motoki Shimizu, Ken-ichi Ikeda, Wen-Hsiung Li, Hitoshi Nakayashiki
Journal: Molecular Biology and Evolution (2023)

Horizontal gene transfer (HGT) is a means of exchanging genetic material asexually. The process by which horizontally transferred genes are domesticated by the host genome is of great interest but is not well understood. In this study, we determined the telomere-to-telomere genome sequence of the wheat-infecting Pyricularia oryzae strain Br48. SNP analysis indicated that the Br48 strain is a hybrid of wheat- and Brachiaria-infecting strains by a sexual or parasexual cross. Comparative genomic analysis identified several megabase-scale "insertions" in the Br48 genome, some of which were possibly gained by HGT-related events from related species, such as P. pennisetigena or P. grisea. Notably, the mega-insertions often contained genes whose phylogeny is not congruent with the species phylogeny. Moreover, some of the genes have a close homolog even in distantly related organisms, such as basidiomycetes or prokaryotes, implying the involvement of multiple HGT events. Interestingly, the levels of the silent epigenetic marks H3K9me3 and H3K27me3 in a genomic region tended to be negatively correlated with the phylogenetic concordance of genes in the same region, suggesting that horizontally transferred DNA is preferentially targeted for epigenetic silencing. Indeed, the putative HGT-derived genes were activated when MoKmt6, the gene responsible for H3K27me3 modification, was deleted. Notably, these genes also tended to be up-regulated during infection, suggesting that they are now under host control and have contributed to establishing a fungal niche. In conclusion, this study suggests that epigenetic modifications have played an important role in the domestication of HGT-derived genes in the P. oryzae genome.
How to define a ‘super-responder’ to biologics in psoriasis studies
Authors: Sarah E Thomas, Juul M P A van den Reek, Marieke M B Seyger, Elke M G J de Jong
Journal: British Journal of Dermatology (2023)

Recently, there has been an increase of publications on super-responders to biologic therapy for psoriasis.In this study, we aimed to contribute to this growing area of research by (i) synthesizing the different definitions of super-responders currently being used in psoriasis literature; and (ii) evaluating the impact of these different definitions on the composition of the super-responder group.
Pregnancy outcomes in patients exposed to baricitinib in clinical trials and during postmarketing surveillance
Authors: Bianca Bergamini, Julien Seneschal, Kristin J Meyers, Frederick Durand, Ewa Haladyj, Gerard Espinosa, Jacob P Thyssen
Journal: British Journal of Dermatology (2023)

Information is needed to manage pregnancies with inadvertent exposure to baricitinib. A total of 117 pregnancies with exposure to baricitinib were identified among patients treated with baricitinib for rheumatoid arthritis, atopic dermatitis, or alopecia areata during clinical trials or in the postmarketing setting, and retrieved from the Eli Lilly global safety database. The clinical outcomes of the pregnancies with reported exposure to baricitinib appear to be comparable to those previously reported with other targeted therapies for immune-mediated diseases or in the general population.